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Intra- and inter-cellular signals that drive hepato-oncogenesis

驱动肝肿瘤发生的细胞内和细胞间信号

基本信息

批准号：
10557925
负责人：
Gen-Sheng Feng
金额：
$ 41.38万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-02-10 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10557925
关键词：
Ablation Animal Model Automobile Driving BAY 54-9085 Cells Cessation of life Chemicals Clinical Complement Data Diethylnitrosamine Disease Environment Environmental Risk Factor Epidermal Growth Factor Receptor Excision Goals Hepatic Hepatocarcinogenesis Hepatocyte Human Immunotherapy Liver Malignant - descriptor Malignant Neoplasms Malignant neoplasm of liver Modeling Molecular Mus NF-kappa B Oncogenes Oncogenic Oncoproteins Oxidative Stress PIK3CA gene Paper Pathogenicity Pathway interactions Patients Pharmacologic Substance Pharmacy (field)Phenotype Play Primary carcinoma of the liver cells Process Proteins Publishing Research Role Sampling Signal Pathway Signal Transduction Sister TP53 gene Testing Therapeutic Transfection Tumor Promotion Tumor Suppressor Proteins beta catenin cancer type chemical carcinogen design experimental study genetic analysis interdisciplinary approach kinase inhibitor liver cancer model liver cancer patient liver inflammation liver injury mouse model novel novel therapeutic intervention single-cell RNA sequencing theories therapeutically effective tumor tumorigenesis tumorigenic

项目摘要

Liver cancer, mainly hepatocellular carcinoma (HCC), has become a most deadly malignant disease worldwide. So far, pharmaceutic inhibition of major oncogenic pathways has achieved little therapeutic benefit to liver cancer patients. We believe this is due to under- appreciation of the complexity in mechanisms of hepato-oncogenesis. In recent experiments, we and others have identified paradoxically anti-oncogenic effects of classical oncogenic molecules, such as c-Met, EGFR, β-catenin, Ikkβ, Jnk, and Shp2, in the liver. Ablating these molecules in hepatocytes enhanced HCC induced by chemical carcinogen DEN. To test a theory that loss of the oncogenic molecules generates an oncogenic microenvironment that promotes DEN-induced HCC, we have established another mouse HCC model, by transfection of oncogenic β-catenin (CAT), c-Met (MET) and PIK3CA (PIK), oncoproteins frequently detected in human HCCs. As expected, MET/CAT-driven HCC was aggravated in β-catenin-deficient liver, due to tumor-promoting factors induced by β-catenin removal. In contrast, Shp2 deletion dramatically suppressed HCC driven by MET/CAT or MET/PIK, despite a similar pro-tumorigenic environment in Shp2-deficient liver. Based on these novel unanticipated data, we propose a new hypothesis that although removal of Shp2 or β-catenin generates cell-extrinsic tumorigenic factors in the hepatic environment, the endogenous Shp2 is indispensable for oncogenic signaling in hepatocytes. To test this hypothesis, we propose three specific aims on this project. Aim 1 is to determine the cell-intrinsic role of Shp2 in hepato-oncogenic signaling. Aim 2 is to determine the cell-autonomous effect of β-catenin in liver tumorigenesis. Aim 3 is to search and identify cell-extrinsic factors induced by loss of the oncoproteins in hepatocytes. The results are expected to be instrumental for design of novel therapeutic strategies for liver cancer by inhibiting both cell-intrinsic oncogenic signals and the secondary environmental factors.

肝癌，主要是肝细胞癌（HCC），已成为最致命的肿瘤。世界范围内的恶性疾病。到目前为止，主要致癌途径的药物抑制对肝癌患者几乎没有治疗效果。我们认为这是由于- 认识肝癌发生机制的复杂性。在最近的实验中，我们和其他人已经发现了经典致癌基因的矛盾的抗癌作用，在肝脏中，细胞因子可以抑制c-Met、EGFR、β-连环蛋白、Ikkβ、Jnk和Shp 2等分子的表达。将这些分子增强化学致癌物DEN诱导的HCC。测试一个致癌分子的丢失产生致癌微环境，促进DEN诱导的HCC，我们建立了另一种小鼠HCC模型，致癌β-连环蛋白（CAT）、c-Met（MET）和PIK 3CA（PIK）癌蛋白的转染在人类肝癌中经常检测到。正如预期的那样，MET/CAT驱动的HCC在 β-连环蛋白缺乏的肝脏，由于β-连环蛋白去除诱导的促肿瘤因子。在相反，Shp 2缺失显著抑制由MET/CAT或MET/PIK驱动的HCC，尽管在Shp 2缺陷的肝脏中存在类似的促肿瘤发生环境。根据这些小说意外的数据，我们提出了一个新的假设，虽然去除Shp 2或β-catenin 在肝脏环境中产生细胞外源性致瘤因子，内源性Shp 2 是肝细胞中致癌信号传导不可或缺的。为了验证这一假设，我们建议这个项目的三个具体目标。目的1是确定Shp 2在细胞内的作用，肝致癌信号。目的二是确定β-连环蛋白在细胞内的自主作用，肝肿瘤发生目的3：寻找和鉴定细胞外因子，肝细胞中的癌蛋白。研究结果可为设计新颖的通过抑制细胞内在致癌信号和二是环境因素。